The retinal photoreceptors are the light-sensing cells that convert complex external visual stimuli to electrical and chemical signals. Degeneration of photoreceptors is the end point of the commonest causes of irreversible blindness including age-related macular degeneration and retinitis pigmentosa, affecting over 50 million people world-wide. In non-mammalian vertebrates such as fish, after retinal injury, resident Muller glia cells in the retina can proliferate, and differentiate into all retinal cell types including photoreceptors and restore visual functions. However, this regenerative potential is almost non-existent in mammals, with only very few new neurons generated after damage. We propose to develop and apply a high throughput screening to identify small molecules that will enhance Muller glia cells reprogramming and differentiation into retinal neurons in mammals, in vitro and in vivo. Identification, optimization, and characterizations of chemical tools for Muller cells reprogramming and differentiation will provide new avenues in developing cell-based therapy as well as conventional small molecule therapeutics for regenerative medicine, and facilitate new understanding of the transdifferentiation mechanisms. Our proposed research will facilitate the development of therapies to restore visual functions that have been lost in human patients with severe blindness. PUBLIC HEALTH RELEVANCE: Identification, optimization, and characterizations of chemical tools for Muller cells reprogramming and differentiation will provide new avenues in developing cell-based therapy as well as conventional small molecule therapeutics for regenerative medicine, and facilitate new understanding of the transdifferentiation mechanisms. Our proposed research will facilitate the development of therapies to restore visual functions that have been lost in human patients with severe blindness.